POS1165 ASSOCIATION OF LDHD RARE VARIANTS WITH EARLY-ONSET GOUT IN TWO FAMILIES WITH AN ADDITIONAL ASSOCIATION OF RHBG VARIANT IN ONE.
Authors: T. Bardin, Y. M. Ducrot, Q. Nguyen, E. Letavernier, H. K. Ea, F. Touzain, D. M. Do, J. Corot, Y. Barguil, A. Biron, P. Richette, C. Collet
Journal: Annals of the Rheumatic Diseases (2022)

Background Elevated lactate is known to favor urine urate reabsorption by the URAT1 urate/anion exchanger. Autosomal recessive gout caused by pathogenic variant in the LDHD gene encoding for D-lactate deshydrogenase has been recently identified in a large consanguineous Bedouin-Israeli kindred (1). Objectives We report here on two families in whom early-onset gout was linked to other variants leading to deficient D-LDH enzymes. Methods Studies of the two families were approved by appropriate Ethics committees. Whole exome sequencing (WES) was used to identify the genetic cause of familial gout. Dosages of D-lactate were performed on immediately frozen serum and urine samples by ELISA, using a D-lactate colorimetric assay kit (Abcam ab83429). Results Family 1 was Melanesian, living in the Lifou island of New Caledonia. The two index patients were two sisters who developed gout at the age of 13 and 16 years respectively. When seen at the ages of 25 and 27 years, they both had severe gout with frequent polyarticular flares, and multiple tophi and destructive arthropathies in the earliest age of onset one. WES, performed on the 2 affected sisters, their non-consanguine parents, and an unaffected brother, showed that the 2 affected sisters carried homozygous rare variant in DLDH gene (NM_153486.3: c.206 C&gt;T; rs1035398551). This variant was at heterozygote level in both parents and absent in the unaffected brother. It was considered as probably damaging according to in silico prediction software. No association with any other gene was found. The c.206C&gt;T variant in LDHD was searched by Sanger sequencing method in 13 other extended family members. One 23 year-old brother of the two diseased sisters with atypical MTP flares, high uricemia and double contours at US examination of his MTPs, carried the c.206 C&gt;T variant at the homozygous level. Three other heterozygous patients were found; two of whom were male with late-onset gout, the third one being a non-menopausal female with no gout. No variant carrier was found in the other 9 genotyped family members. The 3 homozygous patients for the c.206 C&gt;T variant had very high hyperuricemia (range 738-834 was searched by Sanger sequencing method in 13 other extended family members. One 23 year-old brother of the two diseased sisters with atypical MTP flares, high uricemia and double contours at US examination of had very low or no D-lactate in plasma and urine. L-lactate blood and urine levels were normal in all subjects. Family 2 was Vietnamese, living in a remote area of central Vietnam. The two affected children suffered from an extremely severe, destructive gout, which started at the age of 21 years in a daughter and at the age of 9 in her youngest brother, who had developed for the last 3 years, dysarthria, night shakes, memory loss, urine incontinence and an inability to read and count and died at the age of 34, a few months after being seen by us. WES was performed in the two probands, their father and mother (who denied consanguinity), and an unaffected brother. An undescribed variant in LDHD (NM_153486.3: c.1363dupG) was identified in homozygous level in the 2 juvenile gout patients and at the heterozygous level in their 2 parents and unaffected brother. This variant led to a frameshift followed by a stop codon p.(AlaGly432fsTer58). In addition, the two juvenile gout patients were homozygous for an undescribed frameshift (NR_046115.1: c.1064dup) variant of the RHBG gene encoding for a Rhesus Blood Group family ammonium transporter. The two parents carried the heterozygous variant which was not identified in the non-gout brother. Conclusion We report on 2 families in whom autosomal recessive juvenile gout was due to rare or undescribed, damaging LDHD gene variants. In addition, we observed in the Vietnamese family, an additional non-described frameshift homozygous variant in RHBG , the pathophysiological role of which deserves to be investigated. References [1]Drabkin M et al. Hyperuricemia and gout caused by missense mutation in D-lactate dehydrogenase. J Clin Invest. 2019;129:5163-5168 Disclosure of Interests Thomas Bardin Consultant of: leo Pharma, Yves-Marie Ducrot: None declared, Quang Nguyen: None declared, Emmanuel Letavernier: None declared, Hang-Korng Ea: None declared, Frederic Touzain: None declared, Duc Minh Do: None declared, Julien Corot: None declared, Yan Barguil: None declared, Antoine Biron: None declared, Pascal Richette: None declared, Corinne Collet: None declared